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Antioxid Redox Signal. 2010 Mar 1;12(5):583-93. doi: 10.1089/ars.2009.2857.

A differential role for endocytosis in receptor-mediated activation of Nox1.

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1
Department of Medicine, University of Iowa, Iowa City, USA. francis-miller@uiowa.edu

Abstract

Internalization of activated receptors to a compartment enriched with NAPDH oxidase and associated signaling molecules is expected to facilitate regulation of redox-mediated signal transduction. The aim of this study was to test the hypothesis that endocytosis is necessary for generation of reactive oxygen species (ROS) by Nox1 and for redox-dependent signaling in smooth muscle cells (SMCs). Within minutes of treatment with tumor necrosis factor (TNF)-alpha or thrombin, SMCs increased cellular levels of ROS that was inhibited by shRNA to Nox1. Treatment of SMC with TNF-alpha induced a dynamin-dependent endosomal generation of ROS, whereas thrombin-mediated ROS production did not occur within endosomes and was not prevented by dominant-negative dynamin (dn-dynamin), but instead required transactivation of the epidermal growth factor receptor (EGFR). Activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-activating transcription factor-1 (ATF-1) pathway by TNF-alpha and thrombin were both Nox1- and dynamin-dependent. In conclusion, we show that formation of specific ligand-receptor complexes results in spatially distinct mechanisms of Nox1 activation and generation of ROS. These findings provide novel insights into the role of compartmentalization for integrating redox-dependent cell signaling.

PMID:
19737091
PMCID:
PMC2861543
DOI:
10.1089/ars.2009.2857
[Indexed for MEDLINE]
Free PMC Article
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